CN104059069B - Method for preparing one kind of Kage Lei - Google Patents

Method for preparing one kind of Kage Lei Download PDF

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CN104059069B
CN104059069B CN201310368672.3A CN201310368672A CN104059069B CN 104059069 B CN104059069 B CN 104059069B CN 201310368672 A CN201310368672 A CN 201310368672A CN 104059069 B CN104059069 B CN 104059069B
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程刚
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北京康立生医药技术开发有限公司
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Abstract

本发明提供了一种替卡格雷的制备方法,该方法比起已有的路线在步骤上有所缩短,使反应的产率得到大幅的提升,极大地降低了生产成本。 The present invention provides a method for preparing ticagrelor, which are shorter than the conventional route in step, the yield of the reaction to give improved dramatically, greatly reducing the production cost. 本发明所提供的如路线所示的替卡格雷的合成方法在已公开的文献中均没有进行过描述。 The present invention provides alternative synthetic routes as illustrated method Kage Lei were not been described in published literature.

Description

-种替卡格雷的制备方法 - for seed production method of Kage Lei

技术领域 FIELD

[0001] 本发明设及化学领域,具体设及一种替卡格雷的制备方法。 [0001] The present invention is provided and the chemical art, specifically, and one method for preparing Kage Lei provided.

背景技术 Background technique

[0002] 替卡格雷(Ticagrelor;曾用代号:ADZ6140,ARC126532,也有翻译为替格瑞洛),属于环戊基S挫并喀晚类化合物,化学名为(15,25,33,55)-3-[7-[(11?,25)-2-(3,4-二氣苯基)环丙氨基]-5-(硫丙基)-3H-[l,2,3]S挫[4,5-d]喀晚-3-基]-5-(2-¾基乙氧基)环戊烧-1,2-二醇,英文化学名称:(IS,2S,3R,5S)-3-(7-(( IR, 2S)-2-(3,4-dif Iuorophenyl) cyclopropylamino)-5-propylthi〇-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-y1)-5-(2-hy化oxyethoxy)巧clopentane-1,2-diol;分子式:C2出28F2N6O4S;分子量:522.574; CAS登记号:274693-27-5是由英国阿斯利康制药公司(AstraZeneca)研制开发的一种新的治疗急性冠状动脉综合征(日。1116(3〇1'〇]1日巧87]1化加16,4〔5)的药物,该药于2011年7月20日被美国抑A批准上市,商品名为化i 1 in化。 [0002] ticagrelor (Ticagrelor; have used code: ADZ6140, ARC126532, also translated as ticagrelor), belonging to the click cyclopentyl and night setback S based compound, the chemical name (15,25,33,55) 3- [7 - [(11, 25?) - 2- (3,4-gas phenyl) cyclopropylamino] -5- (sulfopropyl) -3H- [l, 2,3] S setback [4,5-d] Ka Night-3-yl] -5- (2-¾-yl-ethoxy) burning cyclopentyl-1,2-diol, English chemical name: (IS, 2S, 3R, 5S) -3- (7 - ((IR, 2S) -2- (3,4-dif Iuorophenyl) cyclopropylamino) -5-propylthi〇-3H- [l, 2,3] triazolo [4,5-d] pyrimidin- 3-y1) -5- (2-hy of oxyethoxy) Qiao clopentane-1,2-diol; molecular formula: C2 out 28F2N6O4S; molecular weight: 522.574; CAS Registry number: 274693-27-5 by AstraZeneca UK one kind (AstraZeneca) developed a new treatment of acute coronary syndrome (May .1116 (3〇1'〇] 1 day Qiao 87] 16,4 [plus 1 of 5) of the drug, the drug in July 2011 May 20 was approved for marketing US suppression A, under the trade name of i 1 in technology.

[0003] 替卡格雷通过防止血液中血小板结块的形成来预防血栓,从而有助于减少再次屯、 血管事件的危险。 [0003] ticagrelor be prevented by preventing the formation of agglomerated platelets in the blood thrombus, Tun again helping to reduce the risk of vascular events. 替卡格雷能可逆性地作用于血管平滑肌细胞(VSMC)上的嚷岭2受体(Purinoceptor2,P2)亚型P2Y12,对AD巧旭的血小板聚集有明显的抑制作用,且口服使用后起效迅速,因此能有效改善急性冠屯、病患者的症状。 Ticagrelor reversibly acts on vascular smooth muscle cells (of VSMC) of cried Ridge 2 receptor (Purinoceptor2, P2) the P2Y12 subtype, the AD clever Asahi significantly inhibited platelet aggregation, and onset of action for oral use quickly, it can effectively improve the symptoms of acute crown Tuen patients. 而因替卡格雷的抗血小板作用是可逆的,其对于那些需在先期进行抗凝治疗后再行手术的病人尤为适用。 And because Kage Lei for antiplatelet effect is reversible, which is particularly applicable to those patients for an early anticoagulation after the surgery.

[0004] 替卡格雷的结构式如下: [0004] Alternatively Kage Lei structural formula is as follows:

[0005] [0005]

Figure CN104059069BD00041

[0006] 阿期利康公司就替卡格雷的制备方法,提交了CN1270590A(申请号CN98809115,发明名称是S挫并[4,5-d]喀晚类化合物、其制备、用途和含有其的药物组合物)。 [0006] A preparation of Zeneca alternative to the method Kage Lei, filed CN1270590A (Application No. CN98809115, entitled setback is S and [4,5-d] Ka Night compounds, their preparation, their use and pharmaceutical containing combination). CN1270590A设及一条化合物I的制备路线(Schemel)CN1270590A中的该条路线步骤长,且其中设及饿酸氧化,DIBAkH还原,铁粉还原等有剧毒或者容易造成大量工业S废的反应,同时该路线总收率低,生产成本高,因此并不能作为合成首选路线。 CN1270590A and provided a compound prepared in Scheme I (Schemel) CN1270590A strip line in a step length, and wherein disposed hungry and acid oxidation, DIBAkH reduction, reduction with iron powder or the like is likely to cause toxic reactions S large number of industrial waste, while the route low overall yield, high production cost, and therefore not as preferred synthetic route.

[000 [000

[000引阿期利康公司就替卡格雷的制备方法,提交了CNlO 1 1 43864A(申请号CN200710152807,发明名称是S挫并喀晚化合物)dCN1270590A到了另外一条化合物I的制备路线(Schemes)。 [000 on the lead A of Zeneca method for preparing the Kage Lei, submitted CNlO 1 1 43864A (Application No. CN200710152807, entitled Ka is S and night setback compound) dCN1270590A addition to the preparation of a compound of Scheme I (Schemes). 该路线同样存在路线较长,总收率偏低的缺点,因此也不适宜作为大规模工业化生产的最优路线。 The route also exists a long line, the total yield disadvantage of the low, and therefore not suitable as the optimal route of large-scale industrial production.

[000; [000;

Figure CN104059069BD00051

[0010]阿期利康公司就替卡格雷的制备方法,提交了CN1 680 340A(申请号CN200510059452,发明名称是S挫并喀晚化合物)。 [0010] A preparation of Zeneca alternative to the method Kage Lei, submitted CN1 680 340A (Application No. CN200510059452, entitled Ka is S and night setback compound).

[0011] 阿期利康公司就替卡格雷中间体的制备方法,提交了CN102149716A(申请号CN200980135932,发明名称是制备[lS-[la,化,30(15*,2帖),50]]-3-[7-[2-(3,4-二氣苯基)-环丙氨基]-5-(丙硫基)-3H-l,2,3-S挫并[4,5-d]喀晚-3-基]-5-(2-¾乙氧基)环戊烧-1,2-二醇的方法及其中间体) [0011] A Zeneca on behalf of preparing intermediates Kage Lei, filed CN102149716A (Application No. CN200980135932, entitled preparation of [lS- [la, of, 30 (15 *, posts 2), 50]] - 3- [7- [2- (3,4-gas-phenyl) - cyclopropylamino] -5- (propylthio) -3H-l, 2,3-S and fell [4,5-d] Ka Night-3-yl] -5- (2-¾ ethoxy) cyclopentyl-1,2-diol burning process and intermediates)

[0012] 上海瞧元化学科技有限公司就替卡格雷的制备方法,提交了CN102675321A(申请号CN201210146500,发明名称是一种替卡格雷的制备方法) [0012] Look-membered Shanghai Chemical Co., Ltd. to a method for the preparation of Kage Lei, filed CN102675321A (Application No. CN201210146500, title of the invention is a method for preparing ticagrelor)

[0013] 阿期利康公司就替卡格雷的制备方法,提交了CN1334816(申请号CN99815926,发明名称是新的S挫并(4,5-D)喀晚化合物)。 [0013] A preparation of Zeneca alternative to the method Kage Lei, filed CN1334816 (Application No. CN99815926, the name of the new invention is frustrated and S (4,5-D) compound Cameroon night). 公开了替卡格雷的合成途径;具体如下: Discloses a synthetic route ticagrelor; follows:

[0014] [0014]

Figure CN104059069BD00061

[0015] W02010030224和W02011017108公开了替卡格雷的合成途径;5-(2-¾乙氧基)环戊烧-1,2-二醇中间体W(S)-2-(叔下氧基甲酯胺基)丙酸为原料,经过10步反应合成得到;中间体4,6-二氯-5-硝基-2-丙硫基喀晚是W 5-硝基-2-丙硫基喀晚-4,6-二醇为原料经过3步合成得到;然后将上述两中间体经过3步合成得到5-丙硫基-3氨-[1,2,3]S挫[4,5-d]喀晚-3-基)-5-(2-¾乙氧基)环戊烧-1,2-二醇。 [0015] W02010030224 and W02011017108 disclose synthetic routes ticagrelor; 5- (2-¾ ethoxy) cyclopentyl-1,2-diol Intermediate burning W (S) -2- (tert-lower group A ester) propanoic acid as starting material, the reaction was synthesized through steps 10; intermediate 4,6-dichloro-5-nitro-2-propane is sulfur Jika Night W 5- nitro-2-propyl disulfide Jika Night 4,6-diol obtained through the 3-step synthesis for the starting material; and the above-described two-step synthesis of intermediate 3 to give 5 through propylthio ammonia -3 - [1,2,3] S setback [4,5- d] Ka Night-3-yl) -5- (2-¾ ethoxy) cyclopentyl-1,2-diol burning. 另外一重要中间体2-(3,4-二氣苯基)环丙基胺是W化)-3-(3,4-二氣苯基)丙締酸为原料,经过5步反应合成而得,最后将运两个片断连接得到目标化合物替卡格雷。 Another important intermediate for 2- (3,4-gas phenyl) cyclopropyl amine is of W) -3- (3,4-gas phenyl) propionic acid association as raw material, and 5 was synthesized from too, finally shipped two fragments were ligated to give the title compound ticagrelor.

[001 d [001 d

Figure CN104059069BD00071

发明内容 SUMMARY

[0017]本发明提供了一种替卡格雷的制备方法,该方法比起已有的路线在步骤上有所缩短,使反应的产率得到大幅的提升,极大地降低了生产成本。 [0017] The present invention provides a method for the preparation of Kage Lei, which are shorter than the conventional route in step, the yield of the reaction to give improved dramatically, greatly reducing the production cost. 本发明所提供的如路线所示的替卡格雷的合成方法在已公开的文献中均没有进行过描述。 The present invention provides alternative synthetic routes as illustrated method Kage Lei were not been described in published literature.

[001引一种替卡格雷的制备方法,其包含如下步骤: [001 primer for preparing one kind of Kage Lei, comprising the steps of:

[0019 [0019

Figure CN104059069BD00081

[002( [002 (

Figure CN104059069BD00091

[0021]其具体过程为: [0021] The specific process is:

[002^ 步骤一:化合物a溶在有机溶剂中,如N,N-二甲基甲酯胺、二氯甲烧,甲苯,乙醇,甲醇等,加入化合物b,b和a的摩尔比为1~5:1,所述反应溫度为-5°C~30°C,反应时间为1~3 小时。 [002 ^ Step a: a compound dissolved in an organic solvent, the molar ratio of the compound added to b, b and a are such as N, N- dimethyl ester amine, methylene burning, toluene, ethanol, methanol, 1 to 5: 1, the reaction temperature is -5 ° C ~ 30 ° C, the reaction time is 1 to 3 hours. 过滤所得固体,即为目标产物C The resulting solid was filtered, the desired product is the C

[002引步骤二:化合物C溶在有机溶剂中,如N,N-二甲基甲酯胺、二氯甲烧,甲苯,乙醇,甲醇等,加入化合物d,d和C的摩尔比为1~8:1,所述反应溫度为-10°C~30°C,反应时间为1~ 5小时。 [Di primers Step 002: the compound C dissolved in an organic solvent, such as N, N- dimethyl ester amine, methylene burning, toluene, ethanol, methanol and the like, compound d, d and 1 molar ratio of C to 8: 1, the reaction temperature is -10 ° C ~ 30 ° C, the reaction time is 1 to 5 hours. 过滤所得固体,即为目标产物e The resulting solid was filtered, e is the desired product

[0024] 步骤S:化合物e用有机溶剂溶解,有机溶剂包括四氨巧喃、N,N-二甲基甲酯胺、N, N-二甲基乙酷胺、甲苯、二氯甲烧、乙醇等。 [0024] Step S: e compound dissolved in organic solvents, including organic solvents clever thiopyran tetraamine, N, N- dimethyl ester amine, N, N- dimethylacetamide cool amine, toluene, dichloromethane burning, ethanol. 加入还原剂,如二氯化锡、氯化锋、氨气等反应1-5小时,溫度控制在10°C-8(rC,浓缩除去有机溶剂,在(TC加入K0H、化OH等碱调节pH值为7-13,有大量固体物质析出,即为目标产物g。 Adding a reducing agent such as stannous chloride, front chloride, ammonia, etc. 1-5 hours the reaction temperature was controlled at 10 ° C-8 (rC, concentrated to remove the organic solvent, the base-mediated (TC added K0H, and the like of OH a pH of 7-13, with a large amount of solid precipitated material, i.e. the desired product g.

[002引步骤四:溫度0°C-8°C范围内,向化合物g中加入10-30倍量的醋酸水溶液,再加入10-30倍量的化N02水溶液,反应时间1-4小时,后加入250-500ml乙酸乙醋和37%碳酸钟水溶液250-500ml,混合物分离,有机相用500-1000水洗,浓缩有机相得目标产物h,此步骤若不控制反应条件,会生成副产物i,将反应环境如溫度、时间控制在W上条件中,可W避免副产物i的生成。 [Cited 002 Step Four: a temperature in the range of C-8 ° C 0 °, was added a solution of compound g in 10-30 fold amount of aqueous acetic acid, then add 10 to 30 times the amount of N02 solution, the reaction time is 1-4 hours, after addition of ethyl acetate 250-500ml acetate and 37% aqueous 250-500ml clock carbonate, the mixture was separated, the organic phase was washed with water 500-1000, the desired product was concentrated organic Xiangde H, if controlling the reaction conditions of this step, by-products generated i the reaction environment such as temperature, time control on the condition of W, W can avoid the formation of byproducts i.

[00%]步骤五:溫度10°C-25°C范围内,化合物h溶于20-30倍量的甲醇中,并向其中加入10-20倍量的3-5mol化盐酸水溶液,揽拌时间为5-8小时,再向其中通入化OH调节pH值为6.5-7.5。 [00%] Step Five: temperature 10 ° C-25 ° C range, Compound h was dissolved in 20 to 30 times amount of methanol, and thereto is added aqueous hydrochloric acid of 10 to 20 times the amount 3-5mol, embrace mix time is 5-8 hours, and thereto into OH and adjusting pH of 6.5-7.5. 蒸出甲醇,加入10-30倍量的乙酸乙醋,分层,有机相用水洗涂蒸出四分之一至二分之一的乙酸乙醋,重新补充新的乙酸乙醋,重复操作2-5次,合并滤液,蒸出部分乙酸乙醋,向其中加入异辛烧,40°C-60°C下揽拌0.5-1小时,冷却至20-30°C,析出大量目标产物j [0027]本发明的创新点 The methanol was distilled off, added 10-30 times amount of acetic acid ethyl ester, layers were separated, the organic phase was washed with water acid ethyl ester coated evaporated to one-quarter hours, replenishing new acetate vinegar, Repeat 2 -5 times the combined filtrate, ethyl acetate was distilled off part of vinegar was added thereto isooctyl burning, embrace stirred 0.5-1 hours at 40 ° C-60 ° C, cooled to 20-30 ° C, the desired product precipitated large J [ innovation 0027] of the present invention

[00%] 1、一般方法在第一步反应中,原料中的苯环取代基为-NH2,进行底物反应,反应时间较长,且溫度相对较高,既不节能又操作不便,本发明用取代基为-N02的原料进行反应, 使得步骤一与步骤二的反应速率得到有效提升,且反应在比较溫和的低溫条件下即可进行操作安全简便,可节省生产成本 [00%] 1, the general method in the first step reaction, the feedstock is a benzene ring substituent group -NH2, the reaction for the substrate, longer reaction times, and the temperature is relatively high, energy-saving and neither maneuver, the present invention as starting material -N02 group substituted with a reaction, a reaction rate such that the step of step two be effectively improved, and the reaction under relatively mild conditions of low temperature to be safe and easy operation, saving production costs

[0029] 2、步骤=中采用乙醇作为反应溶剂,具有溶剂十分溫和的特点,且硝基还原非常彻底,产物纯度较高 [0029] 2, Step = ethanol used as a reaction solvent, a solvent having the characteristics of very moderate, nitro reduction and very thorough, high purity

[0030] 3、步骤四中有效控制反应条件,可有效避免副产物的生成,使之全部转化成目标产物,且在短时间内即可闭环完成 [0030] 3, Step Four reaction conditions effective to produce by-products can be effectively avoided, so that all converted to the desired product and can be completed in a short loop

[0031 ] 4.步骤五通过异辛烧可使得目标产物很快析出,适合工业生产。 [0031] 4. Step Five isooctyl by burning may be such that the desired product soon precipitated suitable for industrial production.

具体实施方式 Detailed ways

[0032] W下提供本发明的具体实施例,W展示可能的实施过程,但并不限制本发明。 Under Example [0032] W provided according to the present invention specifically, W shows a possible embodiment of the process, but do not limit the present invention.

[0033] 具体实施例1 [0033] DETAILED Example 1

[0034] 步骤一: [0034] Step a:

[00巧]室溫下于反应瓶中加入二氯甲烧500ml、化合物a26.7g(0.1mol)、化合物b32.6g (0.15mol),机械揽拌溶解,冰浴冷却至ICTCW下,并控溫滴加S乙胺20.2g,滴毕,回溫至室溫继续揽拌反应化。 [Qiao 00] at room temperature in a reaction flask was added dichloromethane burn 500ml, compound a26.7g (0.1mol), compound b32.6g (0.15mol), stirred mechanically embrace solution was cooled to ice bath under ICTCW, and controls temperature 20.2 g of triethylamine was added dropwise S, dropwise, warmed to room temperature and stirred continued embrace of the reaction. 反应毕,有机相水洗,再用O.lmol/L的盐酸洗涂除去过量的化合物b、最后水洗至中性,无水硫酸钢干燥,浓缩干溶液得到目标产物C,烘干得到白色固体41.9g,收率93.5 %,HPLC纯度98.75 %。 Completion of the reaction, the organic phase washed with water, then O.lmol / L hydrochloric acid wash to remove excess of the compound coating, b, and finally washed with water until neutral, dried over anhydrous sulfate steel, the solution concentrated to dryness to give the desired product C, a white solid was dried to give 41.9 g, yield 93.5%, HPLC purity 98.75%.

[0036] 化合物a为市售品,南京克莱森医药化工有限公司提供,化学名称为4,6-二氯-5-硝基-2-丙硫基喀晚) [0036] Compound A is a commercial product, Claisen Nanjing Pharmaceutical Co., Ltd. to provide chemical name is 4,6-dichloro-5-nitro-2-propylthio Jika night)

[0037] 化合物b为市售品,南京克莱森医药化工有限公司提供,化学名称为2-[[(3aR,4S, 6R,6aS) -6-氨基四氨-2,2-二甲基-4H-环戊締并-1,3-二氧杂环戊烧-4-基]氧基]乙醇[003引化合物c:2-[[(3aR,4S,6R,6aS)-6-(6-氯-5-硝基-2-丙硫基喀晚-4-氨基)四氨-2,2-二甲基-4H-环戊締并-l,3-二氧杂环戊烧-4-基]氧基]乙醇 [0037] Compound b are commercially available, Claisen Nanjing Pharmaceutical Co., Ltd. to provide chemical name is 2 - [[(3aR, 4S, 6R, 6aS) -6- amino-2,2-dimethyl-aminotetrazole -4H- cyclopent-1,3-dioxol association and burning 4-yl] oxy] ethanol [compound 003 primer c: 2 - [[(3aR, 4S, 6R, 6aS) -6- ( 6-chloro-5-nitro-2-propylthio-4-amino sulfur Jika Night) -2,2-dimethyl--4H- tetraammine cyclopentyl and associated -l, 3- dioxol burn - 4- yl] oxy] ethanol

[0039]化合物C 的iHNMR(CDCl3,400Mhz)S :0.96-1.02(t,3H)、1.20(s,6H)、1.33-1.48(m, 2H)、1.40~1.52(m,lH)、2.35-2.46(m,lH)、2.82(s,lH)、3.03-3.10(t,2H)、3.51-3.57(t, 2H)、3.79~3.85(t,2H)、4.16-4.24(q,lH)、4.27-4.37(q,lH)、4.4t-4.46(t,lH)、4.56~ 4.60(d,H)oMs(ESI):449.1181(M+1)。 [0039] Compound C iHNMR (CDCl3,400Mhz) S: 0.96-1.02 (t, 3H), 1.20 (s, 6H), 1.33-1.48 (m, 2H), 1.40 ~ 1.52 (m, lH), 2.35- 2.46 (m, lH), 2.82 (s, lH), 3.03-3.10 (t, 2H), 3.51-3.57 (t, 2H), 3.79 ~ 3.85 (t, 2H), 4.16-4.24 (q, lH), 4.27-4.37 (q, lH), 4.4t-4.46 (t, lH), 4.56 ~ 4.60 (d, H) oMs (ESI): 449.1181 (M + 1).

[0040] [0040]

Figure CN104059069BD00111

[0041] 具体实施例2 [00创步骤二: [0041] Specific Example 2 [00 Chong Step two:

[0043] 室溫下于反应瓶中加入N,N-二甲基甲酯胺50ml、化合物cl5g(0.03mol)、化合物dl0g(0.06mol),化3P〇450g(0.3mol),磁力揽拌至溶解,再加入lgCuI(〇.〇〇5mol),冰浴冷却至20°CW下,缓慢滴加1.8ml N,N'-二甲基乙二胺,滴毕,油浴使体系溫度缓慢上升至100°C 继续揽拌反应化。 [0043] To a reaction flask at room temperature was added N, N- dimethyl ester amine 50ml, compound cl5g (0.03mol), compound dl0g (0.06mol), of 3P〇450g (0.3mol), stirred magnetically to embrace dissolved, then added lgCuI (〇.〇〇5mol), under ice-cooling to 20 ° CW, was slowly added dropwise 1.8ml N, N'- dimethylethylenediamine, dropwise, an oil bath temperature of the system was slowly raised to 100 ° C to continue the reaction mix of olive. 反应毕,冷却至室溫,乙酸乙醋萃取,有机相水洗,无水硫酸钢干燥,浓缩得到目标产物e,烘干得到淡黄色固体粉末Sg,收率88 %,HPLC纯度95.75 %。 Completion of the reaction, cooled to room temperature, extracted with ethyl acetate acetate, the organic phase washed with water, dried over anhydrous sulfate, steel, and concentrated to give desired product E, and drying to give a pale yellow solid powder Sg, yield 88%, HPLC purity 95.75%.

[0044] 化合物d是市售,南京克莱森医药化工有限公司,化学名称(lR,2S)-2-(3,4-二氣苯基)环丙胺)扁桃酸盐 [0044] d is a commercially available compound, Claisen Nanjing Pharmaceutical Co., Ltd., chemical name (lR, 2S) -2- (3,4- two gas phenyl) cyclopropanamine) mandelate

[0045] 化合物e 化学名称:2-[[(3日3,45,61?,6日5)-[6-[(13,25)2-(3,4-二氣苯基)环丙胺]-5-硝基-2-丙硫基喀晚-4-氨基)]四氨-2,2-二甲基-4H-环戊締并-1,3-二氧杂环戊烧-4-基]氧基化醇 [0045] e Compound Chemical Name: 2 - [[(? The 3rd 3,45,61, May 6) - [6 - [(13,25) 2- (3,4-gas phenyl) cyclopropanamine ] -5-nitro-2-propylthio-4-amino Jika Night)] -4H- tetraammine -2,2-dimethyl-cyclopentyl-1,3-dioxole and associated firing -4 - yl] oxy alcohol

[0046] 化合物e 的IhMffi(CDCl3,400Mhz)S:0.69-0.83(m,lH)、0.89-1.03(m,lH)、0.97-1.02(t,3H)、1.21(s,細)、l.:M~1.48(m,2H)、1.71-1.78(m,lH)、1.96-2.08(q,lH)、2.06-2.14(m,lH)、2.67(s,lH)、3.00(s,lH)、3.05-3.12(t,2H)、3.06(s,lH)、3.24-3.36(q,lH)、 3.54-3.57(t,2H)、3.84-3.87(t,2H)、4.20-4.24(m,1H)、4.26-4.29(q,lH)、4.40-4.44(m, IH)、4.59-4.60(d,IH)dMs(ESI):582.2098(M+1)。 [0046] Compound e IhMffi (CDCl3,400Mhz) S: 0.69-0.83 (m, lH), 0.89-1.03 (m, lH), 0.97-1.02 (t, 3H), 1.21 (s, small), l. : m ~ 1.48 (m, 2H), 1.71-1.78 (m, lH), 1.96-2.08 (q, lH), 2.06-2.14 (m, lH), 2.67 (s, lH), 3.00 (s, lH) , 3.05-3.12 (t, 2H), 3.06 (s, lH), 3.24-3.36 (q, lH), 3.54-3.57 (t, 2H), 3.84-3.87 (t, 2H), 4.20-4.24 (m, 1H), 4.26-4.29 (q, lH), 4.40-4.44 (m, IH), 4.59-4.60 (d, IH) dMs (ESI): 582.2098 (m + 1).

[0047] [0047]

Figure CN104059069BD00112

[004引具体实施例3 [0049] 步骤立: [Specific Example 3 004 primer [0049] Step Li:

[0化0] 室溫下于反应瓶中加入无水乙醇50ml、化合物e8g(0.013mol)、SnChTg,磁力揽拌至溶解,油浴使体系溫度缓慢上升至50°C继续揽拌反应化。 [0 of 0] was added to the reaction flask 50ml absolute ethanol at room temperature, the compound e8g (0.013mol), SnChTg, embrace magnetically stirred until dissolved, the oil bath temperature of the system was slowly raised to 50 ° C to continue the reaction mix of olive. 反应毕,冷却至室溫,浓缩除去多余的乙醇,用Imol化的化OH水溶液调节PH值至9,固体析出,烘干得到白色固体粉末即得到目标产物g,3g,收率100 %,HPLC纯度96.33 %。 Completion of the reaction, cooled to room temperature, concentrated to remove excess ethanol, adjusting the PH value of the aqueous Imol OH of 9 to precipitate a solid, i.e., dried to give a white solid powder to give the desired product g, 3g, yield 100%, HPLC purity of 96.33%.

[0051] (化合物g 化学名称:2-[[(3曰3,45,61?,6曰5)-[6-[(11?,25)-2-(3,4-二氣苯基)环丙胺]-4,5-二氨基-2-丙硫基喀晚)]四氨-2,2-二甲基-4H-环戊締并-1,3-二氧杂环戊烧-4-基]氧基化醇 [0051] (g Compound Chemical Name:? 2 - [[(3 said 3,45,61, said 5 6) - [6 - [(11, 25) -2- (3,4-phenyl gas? ) cyclopropanamine] -4,5-diamino-2-propylthio Jika Night)] -4H- tetraammine -2,2-dimethyl-cyclopentyl-1,3-dioxol and associated firing - 4- yl] oxy alcohol

[0052] 化合物g 的iHNMR(CDCl3,400Mhz)S:0.54(s,lH)、0.68-0.80(m,lH)、0.78-0.91(m, 1H)、0.96-1.02(t,3H)、1.21(s,6H)、1.24(s,1H)、1.34~1.48(m,2H)、1.56-1.67(m,2H)、 I.95-2.05(q,IH)、2.15-2.26(m,2H)、2.49(s,lH)'3.05-3.12(t,2H)、3.33-3.44(q,lH)、 3.53-3.59(t,2H)、3.87(s,2H)、3.89-3.95(t,2H)、3.99-4.07(m,lH)'4.40-4.45(t,lH)、 4.46-4.55(q,lH)、4.67-4.70(q,lH)〇Ms(ESI):552.2367(M+l)。 [0052] Compound g of iHNMR (CDCl3,400Mhz) S: 0.54 (s, lH), 0.68-0.80 (m, lH), 0.78-0.91 (m, 1H), 0.96-1.02 (t, 3H), 1.21 ( s, 6H), 1.24 (s, 1H), 1.34 ~ 1.48 (m, 2H), 1.56-1.67 (m, 2H), I.95-2.05 (q, IH), 2.15-2.26 (m, 2H), 2.49 (s, lH) '3.05-3.12 (t, 2H), 3.33-3.44 (q, lH), 3.53-3.59 (t, 2H), 3.87 (s, 2H), 3.89-3.95 (t, 2H), 3.99-4.07 (m, lH) '4.40-4.45 (t, lH), 4.46-4.55 (q, lH), 4.67-4.70 (q, lH) 〇Ms (ESI): 552.2367 (m + l).

[00531 [00531

Figure CN104059069BD00121

[0化4] 具体实施例4 [0 of 4] DETAILED Example 4

[00对步骤四: [00 pairs Step four:

[0056] Egl:5°C下,于反应瓶中加入3g化合物g,30ml醋酸与100mL水,磁力揽拌溶解,通过盐浴冷却至-10°c,控溫向其中加入20g化N〇2/100m化2〇,加完后磁力揽拌反应3小时,加入250ml乙酸乙醋和37%碳酸钟水溶液250ml,使混合物分离,分液,有机相水洗(SOOmL),浓缩、用30mL乙醇/150mL二氯甲烧重结晶得目标产物h,2g,册LC纯度99.58 %,副产物i含量0.08%。 [0056] Egl: at 5 ° C, the reaction flask was added compound 3g g, 30ml of acetic acid and 100mL of water, mixed with a magnetic embrace dissolved by salt bath to -10 ° c, the temperature control was added thereto 20g of N〇2 / 100m of 2〇 increase after magnetic embrace stirred for 3 hours, was added 250ml of acetic acid ethyl ester and 37% carbonate aqueous 250ml clock, the mixture was separated, liquid separation, the organic phase washed with water (SOOmL), concentrated, ethanol 30mL / 150mL recrystallized from methylene chloride to give the desired product burning h, 2g, 99.58% LC purity books, i-product content of 0.08%.

[0057] Eg2:5 °C下,于反应瓶中加入3g化合物g,30ml醋酸与100mL水,磁力揽拌溶解,冰浴冷却至(rC,控溫向其中加入20gNaNaN化/100ml出0,加完后磁力揽拌反应3.5小时,加入250ml乙酸乙醋和37%碳酸钟水溶液250ml,使混合物分离,分液,有机相水洗(SOOmL),浓缩、用20mL正辛烧/IlOmL乙酸重结晶得目标产物1.5g,册LC纯度99.88%,副产物i含量0.03%。 [0057] Eg2: at 5 ° C, the reaction flask was added compound 3g g, 30ml of acetic acid and 100mL of water, mixed with a magnetic embrace solution was cooled to ice bath (rC, the temperature of which was added 20gNaNaN / 100ml as 0, plus after magnetic embrace stirred for 3.5 hours, acetic acid ethyl ester and 250ml of 37% aqueous solution 250ml clock carbonate, the mixture was separated, liquid separation, the organic phase washed with water (SOOmL), concentrated, n-octyl burn 20mL / IlOmL recrystallized from acetic acid targets The product 1.5g, 99.88% LC purity books, i-product content of 0.03%.

[005引E的:5 °C下,于反应瓶中加入3g化合物g,30ml醋酸与100mL水,磁力揽拌溶解,通过冰浴冷却至l0°C,控溫向其中加入20gNaN化/100mL此0,加完后磁力揽拌反应4小时,加入250ml乙酸乙醋和37%碳酸钟水溶液250ml,使混合物分离,分液,有机相水洗(SOOmL),浓缩、用30血1,2-二氯乙烧/130血甲醇重结晶得目标产物h,1.2g,HPLC纯度99.50%,副产物i 含量0.09%。 [005 Primer E is: at 5 ° C, the reaction flask was added compound 3g g, 30ml of acetic acid and 100mL of water, mixed with a magnetic embrace dissolved, cooled by an ice bath to l0 ° C, the temperature of which was added 20gNaN / 100mL this 0, was added after the reaction was stirred for 4 hours embrace magnetic, vinegar was added 250ml ethyl acetate and 250ml of 37% aqueous clock carbonate, the mixture was separated, liquid separation, the organic phase washed with water (SOOmL), concentrated blood with 1,2-dichloro-30 burning acetate / 130 blood was recrystallized from methanol to give the desired product h, 1.2g, HPLC purity 99.50%, 0.09% content of byproducts i.

[0059] Eg4:5 °C下,于反应瓶中加入3g化合物g,30ml醋酸与100mL水,磁力揽拌溶解,通过盐浴冷却至-10°c,控溫向其中加入IOg化N〇2/100m化2〇,加完后磁力揽拌反应3小时,加入250ml乙酸乙醋和37%碳酸钟水溶液250ml,使混合物分离,分液,有机相水洗(SOOmL),浓缩、用30血乙醇/150mL二氯甲烧重结晶得目标产物h,2.2g,HPLC纯度99.83%,副产物i含量0.1%。 [0059] Eg4: ​​at 5 ° C, the reaction flask was added compound 3g g, 30ml of acetic acid and 100mL of water, mixed with a magnetic embrace dissolved by salt bath to -10 ° c, the temperature of which was added IOg N〇2 / 100m of 2〇 increase after magnetic embrace stirred for 3 hours, was added 250ml of acetic acid ethyl ester and 37% carbonate aqueous 250ml clock, the mixture was separated, liquid separation, the organic phase washed with water (SOOmL), concentrated, blood 30 ethanol / 150mL dichloromethane burning target product recrystallization h, 2.2g, HPLC purity 99.83%, i-product content 0.1%.

[0060] E巧:5°C下,于反应瓶中加入3g化合物g,30ml醋酸与100mL水,磁力揽拌溶解,冰浴冷却至0°C,控溫向其中加入IOg化N〇2/100m化2〇,加完后磁力揽拌反应3.5小时,加入250ml 乙酸乙醋和37 %碳酸钟水溶液250ml,使混合物分离,分液,有机相水洗(500mL),浓缩、用3〇1111^乙醇/15〇1111^二氯甲烧重结晶得目标产物11,1.8旨,册1(:纯度99.62%,副产物1含量0.05%。 [0060] E Qiao: at 5 ° C, the reaction flask was added compound 3g g, 30ml of acetic acid and 100mL of water, mixed with a magnetic embrace dissolved, ice-cooled to 0 ° C, was added thereto IOg temperature of N〇2 / 100m of 2〇 increase after magnetic embrace stirred 3.5 hours, acetic acid was added 250ml ethyl acetate and 250ml of 37% aqueous clock carbonate, the mixture was separated, liquid separation, the organic phase washed with water (500 mL), concentrated, ethanol 3〇1111 ^ / ^ 15〇1111 recrystallized from dichloromethane to give the desired product burning 11,1.8 purpose, Volume 1 (purity: 99.62%, a by-product content of 0.05%.

[0061] Eg6:5°C下,于反应瓶中加入3g化合物g,30ml醋酸与100mL水,磁力揽拌溶解,通过冰浴冷却至l〇°C,控溫向其中加入10gNaN02/100mlH20,加完后磁力揽拌反应4小时,加入250ml乙酸乙醋和37%碳酸钟水溶液250ml,使混合物分离,分液,有机相水洗(SOOmL),浓缩、用30血乙醇/150mL二氯甲烧重结晶得目标产物h,1.6g,HPLC纯度99.88%,副产物i含量0.1%。 [0061] Eg6: at 5 ° C, the reaction flask was added compound 3g g, 30ml of acetic acid and 100mL of water, mixed with a magnetic embrace dissolved, cooled by an ice bath to l〇 ° C, to which temperature was added 10gNaN02 / 100mlH20, plus after the reaction was stirred for 4 hours magnetic embrace, vinegar was added 250ml ethyl acetate and 37% aqueous 250ml clock carbonate, the mixture was separated, liquid separation, the organic phase washed with water (SOOmL), concentrated, blood 30 ethanol / 150mL dichloromethane burning recrystallized to give the desired product h, 1.6g, HPLC purity 99.88%, i-product content 0.1%.

[0062] 化合物h化学名称:[3曰3-[3曰日,4日,6日,(11?,25),6曰日]]2-[6-[[7-2-(3,4-二氣苯基)环丙基]氨基-5-(丙基硫代)-3H-l,2,3S挫并[4,5-d]-喀晚-3-基]四氨-2,2-二甲基-4H-环戊締并-1,3-二氧杂环戊烧-4-基]氧基]乙醇。 [0062] Compound h Chemical Name: [3 said 3- [said 3, 4, 6, (11, 25?), Said day 6]] 2- [6 - [[7-2- (3, 4-gas phenyl) cyclopropyl] amino-5- (propylthio) -3H-l, 2,3S setback and [4,5-d] - Ka Night 3-yl] -2 tetraammine , 2-methyl-cyclopent-associative -4H- and 1,3-dioxol-4-burning] oxy] ethanol.

[0063] 化合物h 的lHNMR(CDCl3,400Mhz)S:0.93-1.05(m,2H)、0.96-1.01(t,3H)、1.05-1.17(m,lH)、1.21(S,細)、1.34~1.48(m,2H)、1.92-2.04(m,lH)、2.10-2.22(m,lH)、2.76 (s,lH)、3.05-3.11(t,2H)、3.53-3.59(t,2H)、3.60-3.71(q,lH)、3.84-3.90(t,2H)、4.50-4.56(t,2H)、4.67-4.74(m,lH)、5.49-5.62(m,lH)、7.05-7.11(m,lH)、7.13-7.21(m,lH)〇Ms (ESI):563.2189(M+1)。 [0063] Compound h. LHNMR (CDCl3,400Mhz) S: 0.93-1.05 (m, 2H), 0.96-1.01 (t, 3H), 1.05-1.17 (m, lH), 1.21 (S, small), 1.34 ~ 1.48 (m, 2H), 1.92-2.04 (m, lH), 2.10-2.22 (m, lH), 2.76 (s, lH), 3.05-3.11 (t, 2H), 3.53-3.59 (t, 2H), 3.60-3.71 (q, lH), 3.84-3.90 (t, 2H), 4.50-4.56 (t, 2H), 4.67-4.74 (m, lH), 5.49-5.62 (m, lH), 7.05-7.11 (m , lH), 7.13-7.21 (m, lH) 〇Ms (ESI): 563.2189 (m + 1).

[0064] [0064]

Figure CN104059069BD00131

[00化]具体实施例5 [0066] 步骤五: [Of 00] embodiment 5 [0066] Step Five:

[0067] 室溫下于反应瓶中加入2g化合物h,50mL甲醇,3mol/L的HC148mL,磁力揽拌至溶解,冰浴冷却至20°CW下,揽拌反应15h。 [0067] Compound 2g was added to the reaction flask h at room temperature, 50 mL of methanol, 3mol / L of HC148mL, embrace magnetically stirred until dissolved, under ice-cooling to 20 ° CW, embrace the reaction stirred 15h. 反应完毕后,向其中加入Imol/L的化OH水溶液20mL 调节抑值至7.2左右,蒸出甲醇,加入50mL乙酸乙醋。 After completion of the reaction, 20 mL suppression value adjusted to about 7.2 to which Imol / L of an aqueous solution of OH was added, methanol was distilled off, ethyl acetate was added 50mL acetic acid. 分离水层,有机层用饱和食盐水洗涂, 蒸出20mL乙酸乙醋,重新补充30mL乙酸乙醋,如此重复操作两次,合并滤液,蒸出部分乙酸乙醋,向其中加入异辛烧200mL,通过油浴缓慢升溫至50°C,恒溫揽拌30min,冷却至20°C,目标产物j析出,过滤烘干得到淡黄色粉末1.2g,收率90% ,HPLC纯度97.88%。 The aqueous layer was separated, and the organic layer was washed with brine coating, 20mL acetic acid ethyl ester was distilled off, 30mL acetic acid ethyl ester replenished, so operation was repeated twice, and the combined filtrates were partially evaporated acetic acid ethyl ester, which was added to 200 mL of isooctyl burning, oil bath slowly warmed to 50 ° C, a thermostatic mixing embrace 30min, cooled to 20 ° C, the desired product j to precipitate, filtration and drying to obtain a pale yellow powder 1.2g, yield 90%, HPLC purity 97.88%.

[006引化合物j 化学名称:(15,25,33,55)-3-[7-{[(11?,25)-2-(3,4-二氣苯基)环丙基] 氨基}-5-(丙硫基)-3H-[ 1,2,3]-二挫[4,5-d]喀晚-3-基]-5-(2-¾乙氧基)环戊烧-1,2-二醇。 [Compound 006 j primer Chemical Name: (15,25,33,55) -3- [7 - {[(11, 25?) - 2- (3,4-gas phenyl) cyclopropyl] amino} 5- (propylthio) -3H- [1,2,3] - two setbacks [4,5-d] Ka Night-3-yl] -5- (2-¾ ethoxy) cyclopentyl burn - 1,2-diol.

[0069] 化合物j 的1hNMR((16-DMS0,400M Hz) S: 0.98 (t,3H)、1.73-1.33 (m,4H)、2.07-2.00 (m,1H)'2.29-2.21and2.16-2.09(m,lH)、2.62(d,lH)'2.97-2.80(2H,m)、3.20-3.13化i, m)、3.54-3.46(4H,rn)、3.79-3.73(lH,m)、3.93(lH,s)、4.62-4.53(m,2H)、4.95(q,lH)、 5.05(d,lH)、5.12(d,lH,7=6.4Hz)、7.09-7.00(m,lH)、7.38-7.20(m,2H)、8.96(d,lH)〇Ms (ESI):523.1823(M+1)。 [0069] Compound j is 1hNMR ((16-DMS0,400M Hz) S: 0.98 (t, 3H), 1.73-1.33 (m, 4H), 2.07-2.00 (m, 1H) '2.29-2.21and2.16- 2.09 (m, lH), 2.62 (d, lH) '2.97-2.80 (2H, m), 3.20-3.13 of i, m), 3.54-3.46 (4H, rn), 3.79-3.73 (lH, m), 3.93 (lH, s), 4.62-4.53 (m, 2H), 4.95 (q, lH), 5.05 (d, lH), 5.12 (d, lH, 7 = 6.4Hz), 7.09-7.00 (m, lH) , 7.38-7.20 (m, 2H), 8.96 (d, lH) 〇Ms (ESI): 523.1823 (m + 1).

[0070] [0070]

Figure CN104059069BD00141

[0071 ] 具体实施例6 [0071] DETAILED Example 6

[0072]体外抗凝活性的测定参照Markwardt的凝血酶滴定方法进行。 [0072] In vitro anticoagulant activity is measured with reference to the thrombin titration Markwardt. 于酶标板小孔中加0.5%牛血纤维蛋白原巧Ommol/L Tris肥1缓冲液(P H7.4)配制)200化,再加入100化目标产物j (扣g/mU,充分混匀。用微量进样器吸取标准的凝血酶溶液(IOONIH单位/ml)进行滴定,每次滴定量为扣1(0.5NIH单位),时间间隔为Imin,若在Imin内纤维蛋白原发生凝固,即说明已达到滴定终点。由凝血酶的消耗量可W换算出目标产物j的单位数。由于水赔素与凝血酶是1:1结合,故每消耗一个凝血酶单位(NI皿)相当于一个抗凝血酶单位(ATU),结果:目标产物j纯化后测得比活为9500ATU/mg。 Plus 0.5% bovine fibrinogen clever Ommol / L Tris buffer, 1 fertilizer (P H7.4) formulated in microtiter plate wells) of 200, 100 of the object product was added j (buckle g / mU, mixed well uniform. microsyringe with suction standard thrombin solution (IOONIH units / ml) was titrated, each drop was quantified buckle 1 (0.5NIH unit), the time interval is Imin, when the fibrinogen occurs in the solidification Imin, DESCRIPTION i.e. the titration end point has been reached by the thrombin consumption W may be converted from the number of units of the desired product j lose water due to thrombin factors are 1: 1 binding, so each unit consumes a thrombin (NI dish) corresponds a antithrombin units (ATU), the result: the desired product was purified j measured than live for 9500ATU / mg.

Claims (1)

  1. I. 一种替卡格雷的制备方法,其特征在于: 步骤一: 室温下于反应瓶中加入二氯甲烷500ml、化合物a 26.7g、化合物b 32.6g,机械搅拌溶解,冰浴冷却至l〇°C以下,并控温滴加三乙胺20.2g,滴毕,回温至室温继续搅拌反应2h,反应毕,有机相水洗,再用O.lmol/L的盐酸洗涤除去过量的化合物b、最后水洗至中性,无水硫酸钠干燥,浓缩干溶液得到目标产物c,烘干得到白色固体41.9g, I. for the preparation of one kind of Kage Lei, characterized by the steps of: a: 500ml of dichloromethane was added to the reaction flask at room temperature, 26.7 g Compound A, Compound B 32.6 g, was dissolved with mechanical stirring, ice bath cooled to l〇 ° C below, and temperature control was added dropwise 20.2 g of triethylamine, dropwise, warmed to room temperature and continued stirring the reaction 2h, the reaction was complete, the organic phase washed with water, then washed with a compound of O.lmol / L hydrochloric acid to remove excess, b, Finally washed with water until neutral, dried over anhydrous sodium sulfate, and concentrated to dryness to give the desired product C solution, dried to give a white solid 41.9 g,
    Figure CN104059069BC00021
    步骤二: 室温下于反应瓶中加入N,N-二甲基甲酰胺50ml、化合物c 15g、化合物d 10g,Na3P〇4 50g,磁力搅拌至溶解,再加入IgCuI,冰浴冷却至20°C以下,缓慢滴加1.8ml N,N'-二甲基乙二胺,滴毕,油浴使体系温度缓慢上升至100 °C继续搅拌反应8h,反应毕,冷却至室温,乙酸乙酯萃取,有机相水洗,无水硫酸钠干燥,浓缩得到目标产物e,烘干得到淡黄色固体粉末步骤三: Step two: the reaction flask at rt was added N, N- dimethylformamide 50ml, Compound c 15g, compound d 10g, Na3P〇4 50g, magnetic stirring until dissolved, then add IgCuI, ice-cooling to 20 ° C hereinafter, was slowly added dropwise 1.8ml N, N'- dimethylethylenediamine, dropwise, an oil bath temperature of the system was slowly raised to 100 ° C the reaction was stirred 8h, the reaction was completed, cooled to room temperature, extracted with ethyl acetate, The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to give desired product E, to give a pale yellow solid powder drying step three:
    Figure CN104059069BC00022
    室温下于反应瓶中加入无水乙醇50ml、化合物e 8g、SnCl2 7g,磁力搅拌至溶解,油浴使体系温度缓慢上升至50°C继续搅拌反应3h,反应毕,冷却至室温,浓缩除去多余的乙醇,用Imnl /丨舶NaOH水滚液i固书Pm亩革9.因优妍,屮,.批平徨刹白负因优鉛去即徨S旧烷产物a, 3g The reaction flask was added at room temperature to absolute ethanol 50ml, compound e 8g, SnCl2 7g, magnetic stirring until dissolved, the oil bath temperature of the system was slowly raised to 50 ° C The reaction was stirred 3h, the reaction was completed, cooled to room temperature and concentrated to remove excess ethanol, i roll solution with solid leather book Pm mu Imnl / aqueous NaOH 9. Shu ship preferably by Yan, Cao, batch helpless brake white level due to the negative lead to preferably an alkoxy old product i.e. helpless S a, 3g
    Figure CN104059069BC00023
    步骤四: 5°C下,于反应瓶中加入3g化合物g,30ml醋酸与100mL水,磁力搅拌溶解,通过盐浴冷却至-10°C,控温向其中加入20gNaN02/100mlH20,加完后磁力搅拌反应3小时,加入250ml乙酸乙酯和37 %碳酸钾水溶液250ml,使混合物分离,分液,有机相用500mL水洗,浓缩、用30mL乙醇/150mL二氯甲烷重结晶得目标产物h,2g,HPLC纯度99.58%,副产物i含量0.08% ; 步骤五: Step Four: at 5 ° C, the reaction flask was added compound 3g g, 30ml of acetic acid and 100mL of water, dissolved with magnetic stirring, by salt bath to -10 ° C, to which temperature was added 20gNaN02 / 100mlH20, after adding the magnetic force The reaction was stirred for 3 hours, was added 250ml ethyl acetate and 250ml of 37% aqueous potassium carbonate solution, the mixture was separated, liquid separation, the organic phase was washed with 500mL water, concentrated, ethanol 30mL / 150mL recrystallized from methylene chloride to give the desired product h, 2g, HPLC purity 99.58%, 0.08% content of byproducts i; step five:
    Figure CN104059069BC00031
    室温下于反应瓶中加入2 g化合物h,5 OmL甲醇,3mo I /L的HC148mL,磁力搅拌至溶解,冰浴冷却至20°C以下,搅拌反应15h,反应完毕后,向其中加入lmol/L的NaOH水溶液20mL调节pH值至7.2左右,蒸出甲醇,加入50mL乙酸乙酯,分离水层,有机层用饱和食盐水洗涤,蒸出20mL乙酸乙酯,重新补充30mL乙酸乙酯,如此重复操作两次,合并滤液,蒸出部分乙酸乙酯, 向其中加入异辛烷200mL,通过油浴缓慢升温至50°C,恒温搅拌30min,冷却至20°C,目标产物j析出,过滤烘干得到淡黄色粉末1.2g, The reaction flask 2 g of Compound h at room temperature, 5 OmL methanol, 3mo I / L of HC148mL, magnetic stirring until dissolved, cooled in an ice bath to below 20 ° C, the reaction was stirred for 15H, after the completion of the reaction, thereto was added lmol / 20mL L aqueous NaOH solution to adjust the pH to about 7.2, methanol was distilled off, 50mL of ethyl acetate was added, the aqueous layer separated, the organic layer was washed with saturated brine, ethyl acetate was distilled off 20mL, 30mL of ethyl acetate replenished, repeat operation twice, the combined filtrate, ethyl acetate was distilled off portion, 200 mL of isooctane was added thereto, slowly warmed to 50 ° C by an oil bath at constant temperature with stirring 30min, cooled to 20 ° C, the desired product j to precipitate, filtration and drying pale yellow powder 1.2g,
    Figure CN104059069BC00032
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WO2010030224A1 (en) * 2008-09-09 2010-03-18 Astrazeneca Ab A process for preparing [1s- [1-alpha, 2-alpha, 3-beta (1s*, 2r*) 5-beta] ] -3- [7- [2- (3, 4-dif luorophenyl) -cyclopropylamino] - 5- (propylthio) -3h-1, 2, 3-triazolo [4, 5-d] pyrimidin-3-yl] -5- (2- hydroxyethoxy) cyclopentane-1, 2-diol and to its intermediates
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